Prolonged Perioperative Use of Pregabalin and Ketamine to Prevent Persistent Pain After Cardiac Surgery

Sibtain Anwar, M.D., Ph.D.; Jackie Cooper, Ph.D.; Junia Rahman, M.D.; Chhaya Sharma, M.D.; Richard Langford, M.D.


Anesthesiology. 2019;131(1):119-131. 

In This Article

Abstract and Introduction


Background: Persistent postsurgical pain is common and affects quality of life. The hypothesis was that use of pregabalin and ketamine would prevent persistent pain after cardiac surgery.

Methods: This randomized, double-blind, placebo-controlled trial was undertaken at two cardiac surgery centers in the United Kingdom. Adults without chronic pain and undergoing any elective cardiac surgery patients via sternotomy were randomly assigned to receive either usual care, pregabalin (150 mg preoperatively and twice daily for 14 postoperative days) alone, or pregabalin in combination with a 48-h postoperative infusion of intravenous ketamine at 0.1 mg · kg−1 · h−1. The primary endpoints were prevalence of clinically significant pain at 3 and 6 months after surgery, defined as a pain score on the numeric rating scale of 4 or higher (out of 10) after a functional assessment of three maximal coughs. The secondary outcomes included acute pain, opioid use, and safety measures, as well as long-term neuropathic pain, analgesic requirement, and quality of life.

Results: In total, 150 patients were randomized, with 17 withdrawals from treatment and 2 losses to follow-up but with data analyzed for all participants on an intention-to-treat basis. The prevalence of pain was lower at 3 postoperative months for pregabalin alone (6% [3 of 50]) and in combination with ketamine (2% [1 of 50]) compared to the control group (34% [17 of 50]; odds ratio = 0.126 [0.022 to 0.5], P = 0.0008; and 0.041 [0.0009 to 0.28], P < 0.0001, respectively) and at 6 months for pregabalin alone (6% [3 of 50]) and in combination with ketamine 0% (0 of 5) compared to the control group (28% [14 of 50]; odds ratio = 0.167 [0.029 to 0.7], P = 0.006; and 0.000 [0 to 0.24], P < 0.0001). Diplopia was more common in both active arms.

Conclusions: Preoperative administration of 150 mg of pregabalin and postoperative continuation twice daily for 14 days significantly lowered the prevalence of persistent pain after cardiac surgery.


Persistent postsurgical pain is common and has long-term effects on quality of life.[1] Defined as a new pain developing postoperatively in and around the incision site and persisting for at least 3 months after surgery, it is difficult to treat once established. Prevention of this phenomenon therefore seems attractive given the considerable impact on quality of life.

Up to half of all patients undergoing any type of surgery to the chest may be at risk, and over half of these cases will demonstrate features of neuropathic pain.[2] Postoperative pain can persist for many years—for at least 5 yr after breast surgery, for example—with effects on quality of life.[3,4] Long-term data for pain after cardiac surgery are limited, but level 1 clinical trial data reveal a prevalence of 27 to 41% at 3 postoperative months.[5–7]

Surgical incision is believed to cause hyperalgesia and sensitize the central nervous system.[1] The gabapentinoids are effective in neuromodulating these processes during the treatment of established neuropathic pain.[8] They have also been shown to suppress central sensitization in other centrally driven processes, such as chronic cough, leading to reduced symptoms as well as improved quality of life.[9]

Studies of the preventive effects of gabapentinoids have been limited in terms of duration of perioperative administration, rarely extending beyond a few days.[10] Pregabalin has improved bioavailability, efficacy, and tolerability, as compared to gabapentin, which may be important when considering its prolonged and prophylactic use in pain-free surgical patients.[11] The concept of preventive or protective analgesia is better established with some neuromodulating analgesics, such as ketamine,[12] but surprisingly few studies have taken the approach of combining agents, even in established neuropathic pain, although the exceptions have stood out for their efficacy.[13–15]

Not all surgical patients are destined to develop persistent pain. Predicting a patient's susceptibility may inform the risk: benefit evaluation of any mitigating strategy or medication, especially if the latter has potential for side effects. Preoperative challenges to the nervous system with experimental pain may predict the subsequent development of pain persistence.[16] Sensory testing can also be repeated after surgery to examine putative mechanisms for the transition to persistent pain states.

The aim of this study was to assess the effect of a prolonged regimen of preventive analgesia on chronic pain outcomes, as well as to determine risk factors and potential predictors for this phenomenon. We hypothesized that the use of pregabalin alone or in combination with ketamine would lower the prevalence of persistent pain after cardiac surgery, as compared to usual care.